The incidence of esophageal adenocarcinoma (EA), a rapidly fatal disease, is increasing more rapidly than any other cancer. Much has been learned recently concerning the causes of EA and its main precancerous condition, Barrett's esophagus (BE). In particular, both gastroesophageal reflux disease (GERD) and obesity have been found to be key modifiable risk factors. However, while GERD appears to be crucial to the neoplastic process, only about 10- 15%of persons with long-standing reflux actually develop BE in their lifetimes, and most do not progress to EA. Similarly, the pathways by which obesity increases risk of EA are not known. Understanding the underlying mechanisms by which they affect risk of BE and progression to EA is crucial to identifying effective prevention strategies. Our overarching model is that obesity and GERD act through a network of inter-relating pathways: metabolic abnormalities associated with the insulin resistance syndrome, inflammation and oxidative stress, and alterations in sex steroid hormone levels; and that these processes jointly act to increase mitogenesis, telomere shortening and DNA damage, and inhibit apoptosis. We hypothesize that the effects of obesity and GERD are modified by a number of factors, including diet, physical activity, visceral fat, use of anti-inflammatory medications, and cigarette smoking, and that polymorphisms in inflammatory pathway and related genes are important determinants of susceptibility. We further hypothesize that systemic measures of short- and long-term inflammation and oxidative stress (e.g., serum cytokine and isoprostane levels, leukocyte telomere length) are significant contributors to a personal predictive risk model of neoplastic progression in BE, which we will develop for translation into the clinic. In the renewal period, we propose to evaluate the independent and joint effects of the above factors on risk of neoplastic progression of BE to EA, and risk of developing selected intermediate outcomes as identified by Projects 1 and 3. This will be accomplished through continued follow up and analyses of a well-characterized cohort of over 500 persons with BE followed for up to 17 years. In summary, our project seeks to identify new treatment targets and methods of prevention, along with tools for stratifying patients according to their clinical risk, a vital aid for surveillance, as well as prevention and treatment trials.